Carcinomas typically invade as a cohesive multicellular unit, a process termed collective invasion. It remains unclear how different subpopulations of cancer cells contribute to this process. We ...developed three-dimensional (3D) organoid assays to identify the most invasive cancer cells in primary breast tumors. Collective invasion was led by specialized cancer cells that were defined by their expression of basal epithelial genes, such as cytokeratin-14 (K14) and p63. Furthermore, K14+ cells led collective invasion in the major human breast cancer subtypes. Importantly, luminal cancer cells were observed to convert phenotypically to invasive leaders following induction of basal epithelial genes. Although only a minority of cells within luminal tumors expressed basal epithelial genes, knockdown of either K14 or p63 was sufficient to block collective invasion. Our data reveal that heterotypic interactions between epithelial subpopulations are critical to collective invasion. We suggest that targeting the basal invasive program could limit metastatic progression.
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•Molecularly distinct tumor cells lead collective invasion in breast cancer•Keratin-14+ cells lead collective invasion across major subtypes of breast cancer•Invasive leader cells are generated by induction of a basal epithelial program•Basal epithelial gene expression is required for collective invasion
Collective invasion in breast cancer is led by specialized cancer cells defined by their expression of basal epithelial genes. Targeting the basal epithelial program is sufficient to disrupt the invasive process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite decades of study, there are still many unanswered questions about metastasis, the process by which a localized cancer becomes a systemic disease. One of these questions is the nature of the ...tumor cells that give rise to metastases. Although conventional models suggest that metastases are seeded by single cells from the primary tumor, there is growing evidence that seeding requires the collective action of tumor cells traveling together in clusters. Here, we review this evidence, which comes from analysis of both experimental models and patient samples. We present a model of metastatic dissemination that highlights the activities of clusters of tumor cells that retain and require their epithelial properties.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Most concrete produced today includes either chemical additions to the cement, chemical admixtures in the concrete, or both. These chemicals alter a number of properties of cementitious systems, ...including hydration behavior, and it has been long understood by practitioners that these systems can differ widely in response to such chemicals.
In this paper the impact on hydration of several classes of chemicals is reviewed with an emphasis on the current understanding of interactions with cement chemistry. These include setting retarders, accelerators, and water reducing dispersants. The ability of the chemicals to alter the aluminate–sulfate balance of cementitious systems is discussed with a focus on the impact on silicate hydration. As a key example of this complex interaction, unusual behavior sometimes observed in systems containing high calcium fly ash is highlighted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The aim of this study was to determine the influence of developmental spinal stenosis (DSS) on the risk of re-operation at an adjacent level.
This was a retrospective study of 235 consecutive ...patients who had undergone decompression-only surgery for lumbar spinal stenosis and had a minimum five-year follow-up. There were 106 female patients (45.1%) and 129 male patients (54.9%), with a mean age at surgery of 66.8 years (sd 11.3). We excluded those with adult deformity and spondylolisthesis. Presenting symptoms, levels operated on initially and at re-operation were studied. MRI measurements included the anteroposterior diameter of the bony spinal canal, the degree of disc degeneration, and the thickness of the ligamentum flavum. DSS was defined by comparative measurements of the bony spinal canal. Risk factors for re-operation at the adjacent level were determined and included in a multivariate stepwise logistic regression for prediction modelling. Odds ratios (ORs) with 95% confidence intervals were calculated.
Of the 235 patients, 21.7% required re-operation at an adjacent segment. Re-operation at an adjacent segment was associated with DSS (p = 0.026), the number of levels decompressed (p = 0.008), and age at surgery (p = 0.013). Multivariate regression model (p < 0.001) controlled for other confounders showed that DSS was a significant predictor of re-operation at an adjacent segment, with an adjusted OR of 3.93.
Patients with DSS who have undergone lumbar spinal decompression are 3.9 times more likely to undergo future surgery at an adjacent level. This is a poor prognostic indicator that can be identified prior to index decompression surgery.
To study the associations of lumbar developmental spinal stenosis (DSS) with low back pain (LBP), radicular leg pain, and disability.
This was a cross-sectional study of 2,206 subjects along with ...L1-S1 axial and sagittal MRI. Clinical and radiological information regarding their demographics, workload, smoking habits, anteroposterior (AP) vertebral canal diameter, spondylolisthesis, and MRI changes were evaluated. Mann-Whitney U tests and chi-squared tests were conducted to search for differences between subjects with and without DSS. Associations of LBP and radicular pain reported within one month (30 days) and one year (365 days) of the MRI, with clinical and radiological information, were also investigated by utilizing univariate and multivariate logistic regressions.
Subjects with DSS had higher prevalence of radicular leg pain, more pain-related disability, and lower quality of life (all p < 0.05). Subjects with DSS had 1.5 (95% confidence interval (CI) 1.0 to 2.1; p = 0.027) and 1.8 (95% CI 1.3 to 2.6; p = 0.001) times higher odds of having radicular leg pain in the past month and the past year, respectively. However, DSS was not associated with LBP. Although, subjects with a spondylolisthesis had 1.7 (95% CI 1.1 to 2.5; p = 0.011) and 2.0 (95% CI 1.2 to 3.2; p = 0.008) times greater odds to experience LBP in the past month and the past year, respectively.
This large-scale study identified DSS as a risk factor of acute and chronic radicular leg pain. DSS was seen in 6.9% of the study cohort and these patients had narrower spinal canals. Subjects with DSS had earlier onset of symptoms, more severe radicular leg pain, which lasted for longer and were more likely to have worse disability and poorer quality of life. In these patients there is an increased likelihood of nerve root compression due to a pre-existing narrowed canal, which is important when planning surgery as patients are likely to require multi-level decompression surgery. Cite this article:
2021;103-B(1):131-140.
Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct ...clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14⁺ cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14⁺ epithelial tumor cell clusters disseminate collectively to colonize distant organs.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The aim of this study was to assess whether supine flexibility predicts the likelihood of curve progression in patients with adolescent idiopathic scoliosis (AIS) undergoing brace treatment.
This was ...a retrospective analysis of patients with AIS prescribed with an underarm brace between September 2008 to April 2013 and followed up until 18 years of age or required surgery. Patients with structural proximal curves that preclude underarm bracing, those who were lost to follow-up, and those who had poor compliance to bracing (<16 hours a day) were excluded. The major curve Cobb angle, curve type, and location were measured on the pre-brace standing posteroanterior (PA) radiograph, supine whole spine radiograph, initial in-brace standing PA radiograph, and the post-brace weaning standing PA radiograph. Validation of the previous in-brace Cobb angle regression model was performed. The outcome of curve progression post-bracing was tested using a logistic regression model. The supine flexibility cut-off for curve progression was analyzed with receiver operating characteristic curve.
A total of 586 patients with mean age of 12.6 years (SD 1.2) remained for analysis after exclusion. The baseline Cobb angle was similar for thoracic major curves (31.6° (SD 3.8°)) and lumbar major curves (30.3° (SD 3.7°)). Curve progression was more common in the thoracic curves than lumbar curves with mean final Cobb angles of 40.5° (SD 12.5°) and 31.8° (SD 9.8°) respectively. This dataset matched the prediction model for in-brace Cobb angle with less mean absolute error in thoracic curves (0.61) as compared to lumbar curves (1.04). Reduced age and Risser stage, thoracic curves, increased pre-brace Cobb angle, and reduced correction and flexibility rates predicted increased likelihood of curve progression. Flexibility rate of more than 28% has likelihood of preventing curve progression with bracing.
Supine radiographs provide satisfactory prediction for in-brace correction and post-bracing curve magnitude. The flexibility of the curve is a guide to determine the likelihood for brace success. Cite this article:
2020;102-B(2):254-260.
Modern genomics sequencing techniques have provided a massive amount of protein sequences, but experimental endeavor in determining protein structures is largely lagging far behind the vast and ...unexplored sequences. Apparently, computational biology is playing a more important role in protein structure prediction than ever. Here, we present a system of de novo predictor, termed NiDelta, building on a deep convolutional neural network and statistical potential enabling molecular dynamics simulation for modeling protein tertiary structure. Combining with evolutionary-based residue-contacts, the presented predictor can predict the tertiary structures of a number of target proteins with remarkable accuracy. The proposed approach is demonstrated by calculations on a set of eighteen large proteins from different fold classes. The results show that the ultra-fast molecular dynamics simulation could dramatically reduce the gap between the sequence and its structure at atom level, and it could also present high efficiency in protein structure determination if sparse experimental data is available.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of this study was to investigate whether including the stages of ulnar physeal closure in Sanders stage 7 aids in a more accurate assessment for brace weaning in patients with adolescent ...idiopathic scoliosis (AIS).
This was a retrospective analysis of patients who were weaned from their brace and reviewed between June 2016 and December 2018. Patients who weaned from their brace at Risser stage ≥ 4, had static standing height and arm span for at least six months, and were ≥ two years post-menarche were included. Skeletal maturity at weaning was assessed using Sanders staging with stage 7 subclassified into 7a, in which all phalangeal physes are fused and only the distal radial physis is open, with narrowing of the medial physeal plate of the distal ulna, and 7b, in which fusion of > 50% of the medial growth plate of distal ulna exists, as well as the distal radius and ulna (DRU) classification, an established skeletal maturity index which assesses skeletal maturation using finer stages of the distal radial and ulnar physes, from open to complete fusion. The grade of maturity at the time of weaning and any progression of the curve were analyzed using Fisher's exact test, with Cramer's V, and Goodman and Kruskal's tau.
We studied a total of 179 patients with AIS, of whom 149 (83.2%) were female. Their mean age was 14.8 years (SD 1.1) and the mean Cobb angle was 34.6° (SD 7.7°) at the time of weaning. The mean follow-up was 3.4 years (SD 1.8). At six months after weaning, the rates of progression of the curve for patients weaning at Sanders stage 7a and 7b were 11.4% and 0%, respectively for those with curves of < 40°. Similarly, the rates of progression of the curve for those being weaned at ulnar grade 7 and 8 using the DRU classification were 13.5% and 0%, respectively. The use of Sanders stages 6, 7a, 7b, and 8 for the assessment of maturity at the time of weaning were strongly and significantly associated (Cramer's V 0.326; p = 0.016) with whether the curve progressed at six months after weaning. Weaning at Sanders stage 7 with subclassification allowed 10.6% reduction of error in predicting the progression of the curve.
The use of Sanders stages 7a and 7b allows the accurate assessment of skeletal maturity for guiding brace weaning in patients with AIS. Weaning at Sanders stage 7b, or at ulnar grade 8 with the DRU classification, is more appropriate as the curve did not progress in any patient with a curve of < 40° immediately post-weaning. Thus, reaching full fusion in both distal radial and ulnar physes (as at Sanders stage 8) is not necessary and this allows weaning from a brace to be initiated about nine months earlier. Cite this article:
2021;103-B(1):141-147.
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